Induction and Propagation of Ferroptosis Evasion by FTH1P7 Drives Sorafenib Resistance in Hepatocellular Carcinoma.
Sorafenib refractoriness severely compromises therapeutic efficacy in hepatocellular carcinoma (HCC). This study identifies ferritin heavy chain 1 pseudogene 7 (FTH1P7) as a critical driver and propagator of sorafenib resistance. FTH1P7 was significantly upregulated in HCC cells resistant to sorafenib. Mechanistically, the self-sustaining FTH1P7/microRNA-182-5p/FOXC1 positive feedback loop maintained high FTH1P7 expression levels in resistant cells. Elevated FTH1P7 functioned as a competing endogenous RNA to the mRNA of its parental gene, ferritin heavy chain 1 (FTH1). Increased FTH1 levels enhanced Fe2+ oxidation, thereby inhibiting ferroptosis-a key anticancer mechanism of sorafenib-thereby conferring resistance. Furthermore, exosomes derived from resistant cells transferred FTH1P7 to sorafenib-sensitive cells, thereby horizontally propagating resistance. To counter sorafenib resistance, we developed a nanoliposome co-delivering sorafenib and FTH1P7-targeting siRNA (SR-siFTH1P7-LIP). This nanomedicine synergistically and effectively silenced FTH1P7 expression and reversed resistance. These results elucidate novel mechanisms of sorafenib resistance, involving FTH1P7-mediated induction and exosomal propagation of ferroptotic resistance, and propose a promising nanomedicine-based strategy to combat sorafenib refractoriness in HCC.